The long term goal of this application is to greater elucidate the mechanisms and biological significance of crosstalk between the innate immune response and nuclear hormone receptors in host defense against infections and in pathogen-associated metabolic diseases. Preliminary data in our lab has identified a novel Interferon Regulatory Factor 3(IRF3)-dependent but type I interferon independent pathway induced during innate immune response to viral product stimulation or viral infection, which can lead to strong transcriptional repression of Retinoid X Receptor a (RXRa). As RXRa is the major heterodimer partner for most of the nuclear hormone receptors involved in numerous cellular metabolic processes, we hypothesize that repression of RXRa and its regulated genes during viral infections can contribute to the pathogenesis of viral associated metabolic diseases such as Reye[unreadable]s Syndrome, a hepatotoxicity disease that occurs when children are given aspirin in the context of a viral infection. Furthermore, additional preliminary data in our lab showed that nuclear hormone receptor agonists can suppress the induction of antiviral genes and promote viral replications. We therefore also hypothesize that repression of nuclear hormone receptors by the innate immune response may contribute to a proper anti-viral response. In this application, we will determine the roles and mechanisms of the crosstalk between anti-viral immune response and nuclear hormone receptors in both viral associated hepatotoxicity and host defense against viral infections. We plan to first develop mouse models that mimic Reye[unreadable]s Syndrome and acetaminophen (APAP)-induced hepatotoxicity. We will then use these mouse models to determine the molecular mechanisms responsible for hepatotoxicity resulting from the crosstalk between anti-viral immune response and nuclear hormone receptors. Finally, we will analyze the effects of nuclear hormone receptors and their agonists on anti-viral innate immune responses to determine if the repression of nuclear hormone receptors by innate immune response is necessary for the proper host defense against viral infections. We believe our investigation of the crosstalk between the innate immune response and nuclear hormone receptor-mediated metabolism will not only help us to understand the mechanisms responsible for viral induced metabolic diseases and drug induced immuno-suppressions but will also provide novel strategies to prevent or treat patients with viral infections and their associated metabolic diseases.